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WO2019136247A1 - Polymères hautement adhérents pour revêtements de dispositif orthopédique - Google Patents

Polymères hautement adhérents pour revêtements de dispositif orthopédique Download PDF

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Publication number
WO2019136247A1
WO2019136247A1 PCT/US2019/012346 US2019012346W WO2019136247A1 WO 2019136247 A1 WO2019136247 A1 WO 2019136247A1 US 2019012346 W US2019012346 W US 2019012346W WO 2019136247 A1 WO2019136247 A1 WO 2019136247A1
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WIPO (PCT)
Prior art keywords
copolymer
carbons
alkyl
orthopedic device
formula
Prior art date
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Ceased
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PCT/US2019/012346
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English (en)
Inventor
Alexy A. VERTEGEL
Igor A. Luzinov
Christopher E. CROSS
Dmitry GIL
Nikolay BORODINOV
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Clemson University
MUSC Foundation for Research and Development
Original Assignee
Clemson University
MUSC Foundation for Research and Development
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Publication date
Application filed by Clemson University, MUSC Foundation for Research and Development filed Critical Clemson University
Priority to US16/959,562 priority Critical patent/US20210077668A1/en
Publication of WO2019136247A1 publication Critical patent/WO2019136247A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/08—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing solids as carriers or diluents
    • A01N25/10—Macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
    • A61B17/58—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor for osteosynthesis, e.g. bone plates, screws or setting implements
    • A61B17/68—Internal fixation devices, including fasteners and spinal fixators, even if a part thereof projects from the skin
    • A61B17/84—Fasteners therefor or fasteners being internal fixation devices
    • A61B17/846—Nails or pins, i.e. anchors without movable parts, holding by friction only, with or without structured surface
    • A61B17/848—Kirschner wires, i.e. thin, long nails
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/10—Esters
    • C08F220/26—Esters containing oxygen in addition to the carboxy oxygen
    • C08F220/28—Esters containing oxygen in addition to the carboxy oxygen containing no aromatic rings in the alcohol moiety
    • C08F220/285—Esters containing oxygen in addition to the carboxy oxygen containing no aromatic rings in the alcohol moiety and containing a polyether chain in the alcohol moiety
    • C08F220/286—Esters containing oxygen in addition to the carboxy oxygen containing no aromatic rings in the alcohol moiety and containing a polyether chain in the alcohol moiety and containing polyethylene oxide in the alcohol moiety, e.g. methoxy polyethylene glycol (meth)acrylate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B2017/00831—Material properties
    • A61B2017/00889—Material properties antimicrobial, disinfectant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/06—Coatings containing a mixture of two or more compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/24—Materials or treatment for tissue regeneration for joint reconstruction

Definitions

  • the present invention is related to a coating for medical implants, particularly orthopedic devices, wherein the coating has superior adhesion to the medical implant and the coating is capable of slow release of antimicrobials thereby mitigating infection rates.
  • Orthopedic implants are available for many applications including joint replacements, bone repair fixtures and the like without limit thereto.
  • orthopedic implants there are two general classes of orthopedic implants with one class being exclusively internal and typically permanent, such as a hip joint or shoulder joint, and the other being partially internal and temporary, such as Kirshner wires. All orthopedic implants are capable of housing bacteria and other undesirable materials and therefore infection due to an orthopedic implant is a particularly severe problem.
  • Pin site infections arise from the use of percutaneous pinning techniques such as those employed in skeletal traction, percutaneous fracture pinning, external fixation for fracture stabilization or complex deformation reconstruction. These sites are niduses for infection because the skin barrier is disrupted which allows for bacteria to enter at the junction of the skin and pin. After external fixation the rate of pin site infections is usually high and, in some circumstances and techniques, approaches 100%. Following pin site infection the pin may become loose which causes increased pain and the integrity of the fracture fixation may be compromised resulting in structural deformity and inferior clinical results. The excessive pain is also related to increased narcotic usage which is a critical secondary consideration.
  • pin site infections While many of the pin site infections are treatable with adequate wound care and oral antibiotics, osteomyelitis and deep soft tissue infections may occur with evidence of up to 4% of the cases escalating to a requirement for a more complex care plan. Due to the morbidity and costs associated with its sequelae, strategies to reduce pin site infections are vital.
  • Kirshner wires are sharpened pins, typically of stainless steel or titanium, which are inserted into the body for holding or positioning bones or for immobilization of a joint. K-wires typically extend outside the body thereby creating an air interface where the orthopedic device and surgical site meet and provide a potential site for infection. Therefore, even if the surgical procedure is accomplished without introduction of infection, the surgical site is subject to post- surgical infection.
  • the infection rate following a K-wire procedure ranges from 11 % to 100% depending on the procedure, facility and other parameters. Infection can result in sepsis, osteomyelitis and mortality if not treated properly. It has been estimated that the economic burden of infections following K-wire procedures will exceed one billion dollars by 2020 in the U.S. alone.
  • Staphylococcal infections account for about 80% of the infections observed after K-pin procedures. Mitigating this infection alone would have a significant impact on the number and severity of post-surgical infections observed in K-wire recipients. There have been many efforts associated with the formation of coatings, particularly on K-wires, to form a surface which is less susceptible to absorption of bacteria or capable of being impregnated with antimicrobials.
  • a coating which is particularly suitable for orthopedic inserts wherein the coating has sufficient adhesion to survive implant and the coating provides for a slow release of antimicrobials.
  • the present invention is related to a coating for orthopedic implants wherein the coating has superior adhesion and provides for a slow release of antimicrobials.
  • the present invention is related to a coating for orthopedic implants, and improved orthopedic implants comprising a coating, wherein the coating has sufficient adhesion to the orthopedic implant to survive surgical implant and the coating comprises antimicrobials which are released at a controlled rate.
  • a particular feature of the invention is the ability to adjust the release rate of a specific antimicrobial by alteration of the coating.
  • an orthopedic implant comprising a surface with a coating on the surface wherein the coating comprises a copolymer defined by Formula I: Aw-Bx-Cy-D z
  • A comprises an epoxy group or alkoxy silyl group
  • B comprises a hydrophobic group
  • C is an optional cross-linker
  • D comprises a hydrophilic group
  • w is at least 0.1 to no more than 0.9 with the proviso that at least one of x or z is not zero;
  • x is up to 0.9
  • y is up to 0.3
  • z is up to 0.9.
  • A comprises an epoxy or alkoxy silyl group
  • B comprises a hydrophobic group
  • C is an optional cross-linker
  • D of Formula I comprises a hydrophilic group
  • w is at least 0.1 to no more than 0.9 with the proviso that at least one of x or z is not zero;
  • x is up to 0.9
  • y is up to 0.3
  • Fig. 1 is a graphical representation of an embodiment of the invention.
  • Fig. 2 is a graphical representation of an embodiment of the invention.
  • Fig. 3 is a graphical representation of an embodiment of the invention.
  • Fig. 4 is a graphical representation of an embodiment of the invention.
  • the present invention is related to improved orthopedic devices
  • the coating is capable of slow release of a loaded drug.
  • drugs selected from the group consisting of anti-inflammatory drugs, antimicrobial drugs, anticancer drugs, antioxidant drugs or growth factor drugs with any other compatible drug being suitable for use.
  • the present invention is specific to a polymeric coating comprising a copolymer formed by the polymerization of a monomer comprising an epoxy terminal group with a mixture of monomers comprising hydrophobic groups and hydrophilic groups.
  • the epoxy termination crosslinks with hydroxyl groups on the metal thereby providing adhesion of the polymeric matrix to the metal.
  • the hydrophobic and hydrophilic components of the co-polymer allow for control of antimicrobial release rate and drug affinity.
  • the coating on the implant surface will be fabricated using a grafting method supplemented with cross-linking of the coating.
  • the grafting method includes reaction of functionalized polymers with complimentary functional groups located on the substrate surface.
  • One of the advantages of the grafting method is that the reaction does not require elaborate synthetic procedures. The synthesis and modification are sequential and therefore the conditions of the synthesis are not complicated by the presence of the substrate being coated which increases flexibility with regards to the materials which can be easily coated.
  • the surface modification process is preferably accomplished by dissolving previously prepared copolymers in a solvent, preferably water.
  • the copolymer is then deposited as a film on the surface being modified by any suitable technique preferably selected from dip-coating, spray-coating or drop-casting.
  • the coating thickness can be easily controlled by copolymer concentration and other processing parameters such as residence time in solution or deposition amount.
  • the polymer is preferable formed by radical polymerization which is well known to those of skill in the art and further detail thereof is not necessary.
  • a particularly preferred polymer is defined by Formula I:
  • the copolymer can be a random copolymer wherein A, B, C and D are randomly distributed, a block co-polymer comprising discrete blocks of each monomer, periodic copolymers wherein the monomers are arranged in a repeating sequence, statistical copolymers wherein the sequence follows a statistical rule or combinations thereof throughout the polymer chain.
  • Component A of Formula I comprises an epoxy group and is represented in the copolymer by the formula:
  • X is O or N and preferably O
  • R 1 is a hydrogen or alkyl of up to 4 carbons
  • R 2 is a linking group preferably selected from alkyl of 2 to 5 carbons and -C(0)-0- CH 2 -;
  • R 12 is an alkyl of up to 10 carbons which may be substituted.
  • Epoxy groups reacts with the metal surface and provides for strong adhesion of the coating to the metal surface. Epoxy groups also provide excellent storage properties and can remain stable for as much as six months in water. Under acid or base conditions the ring opens and is reactive with any nucleophilic group such as the hydroxyl groups on the surface of a metal.
  • a particularly preferred component A is a glycidyl methacrylate (PGMA) moiety represented in the polymer by:
  • component A Another particularly preferred group for component A is an alkoxy silyl.
  • Alkoxy silyls provide strong adhesion of the coating to the metal surface and ensures structural integrity of the coating during the application of shear and bending forces.
  • a particularly preferred alkoxy silyl group is 3-(trimethoxysilyl) methacrylate represented by the following structure:
  • Component B of Formula I comprises a hydrophobic group represented in the copolymer by the formula:
  • R 3 is a hydrogen or alkyl of up to 4 carbons
  • R 4 is a linking group preferably selected from alkyl of 2 to 5 carbons and -C(0)-0- Chh-;
  • R 5 is an alkyl of 6 to 100 carbons and more preferably 10 to 100 carbons.
  • a particularly preferred component B is lauryl methacrylate (LMA) represented by the polymerized monomer:
  • Component C of Formula I is an optional cross-linker, and preferably a UV cross-linker, capable of crosslinking with other groups within the copolymer thereby providing additional adhesion or polymeric strength.
  • Component C of Formula I is represented in the polymer by the formula:
  • R 6 is a hydrogen or alkyl of up to 4 carbons; and R 7 is a linking group preferably selected from alkyl of 2 to 5 carbons and -C(0)-0- CH 2 -.
  • a particularly preferred component C is allyl methacrylate (AMA) represented by the polymerized monomer:
  • Component D of Formula I comprises a hydrophilic group providing water solubility, swellability, protein repellency and a matrix.
  • Compound D is represented in the polymer by the formula:
  • R 8 is a hydrogen or alkyl of up to 4 carbons
  • R 9 is a linking group selected from alkyl of 2 to 5 carbons and -C(O)-;
  • R 10 is a hydrogen or alkyl of up to 4 carbons
  • R 11 is a hydrogen or alkyl of up to 4 carbons
  • n is at least 2 to no more than 25.
  • Poly (oligo(ethylene glycol) methyl ether methacrylate) (POEGMA) as component D has particularly desirable protein/cell repellency properties and the ability to compatibilize materials with water.
  • the reactive methacrylate moiety is capable of undergoing polymerization while quite long poly ethylene glycol moieties provide water compatibility to the copolymer.
  • the poly ethylene glycol moieties are known to have low toxicity and do not trigger immune system responses.
  • a particularly preferred component D is polymerized ethylene glycol methacrylate (OEGMA) represented by the polymerized monomer:
  • n is preferably an integer sufficient to achieve a molecular weight of 300 to 2000 and preferably 800 to 1200.
  • Particularly preferred component D is OEGMA wherein n is selected from the integers 2-9, or combinations thereof, wherein the hydrophilicity increases with increasing n.
  • w is at least 0.1 to no more than 0.9 with at least one of x or z is not zero. Below about 0.1 mole fraction the number of epoxy groups is insufficient to form an adhesive bond to the metal. Above a mole fraction of about 0.9 there is insufficient hydrophobic or hydrophilic moieties to absorb a sufficient amount of antimicrobial to be beneficial. More preferably, w is at least 0.1 to no more than 0.85, even more preferably at least 0.1 to no more than 0.73, even more preferably at least 0.1 to no more than 0.6 and most preferably at least 0.1 to no more than 0.3.
  • x is up to 0.9 and preferably at least 0.01 up to 0.9.
  • the molar ratio of component B is determined based on the degree of hydrophobicity required to achieve the release rate. A higher portion of the hydrophobic moiety will slow water absorption and therefore decrease the release rate of hydrophilic antimicrobials. If the hydrophobic moiety is too high the antimicrobials cannot be absorbed in the copolymer. More preferably, x is at least 0.2 to no more than 0.8 and even more preferably at least 0.5 to no more than 0.7.
  • y is up to 0.3 and preferably 0.001 up to 0.3.
  • the optional cross-linker provides additional intra-polymer cross-linking which increases the mechanical robustness of the polymer. If the degree of cross-linking is excessive the microbacterial is unable to be absorbed and released from the copolymer matrix. More preferably, y is no more than 0.05.
  • the optional cross-linker allows for secondary cross-linking if necessary such as by UV activation.
  • z is up to 0.9 and preferably 0.01 up to 0.9.
  • the molar ratio of component D is determined based on the degree of hydrophilicity required to achieve the release rate. A higher portion of the hydrophilic moiety will increase water absorption and therefore increase the release rate of hydrophilic
  • z is at least 0.1 to no more than 0.5 and even more preferably at least 0.1 to no more than 0.3.
  • the copolymer is formed on the surface of the metal to form an adequate coating which preferably does not exceed about 0.1 wt% of the mass of the K-wire or about 100 mM thickness. Above a thickness of about 100 pm the coating becomes less robust and deterioration is observed upon insertion through a SeptaTM used to simulate surgical insertion. More preferably, the thickness of the coating is about 0.1 to 5 pm and even more preferably about 0.5 to 1 pm.
  • the surface of the metal can be used as is or treated to increase the number of surface hydroxyl groups thereby increasing the bonding sites available for reaction with the epoxy or alkoxy silyl group.
  • the surface may be on an exclusively internal orthopedic device, such as a replacement joint, or a partially external orthopedic device such as a Kirshner wire.
  • the surface is not particularly limited herein with the proviso that the surface have cross-linkable groups on the surface such as hydroxyl groups. Titanium, stainless steel and ceramic surfaces are particularly preferred.
  • Control K-wires were coated with monolaurin (ML), a natural antimicrobial agent active against S. aureus.
  • Sample K-wires were coated with a copolymer formed from 20 mole percent glycidyl methacrylate, 60 mole percent ethylene glycol methacrylate and 20 mole percent ethylene glycol methacrylate available as OEGMA 950 from Sigma Aldrich.
  • OEGMA 950 from Sigma Aldrich.
  • Samples were prepared including a control K-wire (Control), a K-wire coated with ML only but not passed through a SeptaTM (ML Coated), a sample treated with ML and passed through a SeptaTM (ML Coated Septa), and inventive examples comprising ML with polymer, using OEGMA as the hydrophilic moiety (ML/POEGMA).
  • Some of the inventive samples were passed through a SeptaTM (ML/POEGMA Septa). The samples were all incubated in S. aureus for 48 hours.
  • the results are provided graphically in Fig. 4. As realized from the results presented in Fig. 4 the ML coated sample demonstrates effective resistance unless passed through a SeptaTM suggesting the ML coating is removed or otherwise rendered ineffective.
  • the inventive examples are not negatively impacted by passing through the SeptaTM which indicates a robust coating on the surface.
  • Copolymer A comprising a 15/66/19 molar ratio of GMA, OEGMA and LMA.
  • Copolymer A was deposited from a methylether ketone (MEK) solvent with a 2.5 wt% polymer concentration. The coating was thermally treated at 80°C for 5 hours to crosslink the reactive groups. The polymer thickness was about 900 nm as determined by atomic force microscopy. The polymer layer was loaded with monolaurin, as a water insoluble antimicrobial, and vancomycin, as a water-soluble anti-microbial to test release rate. The antimicrobials were added by introducing the coated polymer to an MEK solution comprising the antimicrobial.
  • MEK methylether ketone
  • Copolymer A was compared to poly(lactide-co- glycolide) PLGA) with monolaurin as a model antimicrobial additive.
  • S. aureus biofilms were grown by statically incubating a S. Aureus suspension with 1 cm K-wire pieces for 48 hours.
  • Monolaurin incorporated into both coatings, and a coating of monolaurin with no polymer layer were all efficient in preventing biofilm formation.
  • the PLGA based coating lost the antimicrobial activity while the sample utilizing Copolymer A remained efficient against biofilm formation.
  • K-wires were prepared as in Example 3 with vancomycin as the
  • the K-wires were drilled into a mechanically equivalent femoral bone construct available from Sawbones USA as Model #3414. The wires were then removed from the drill, rinsed by deionized water and cut into pieces. The pieces that were exposed to the bone were placed into test tubes containing 10 7 colony forming units (CFU) if S. aureus. Only the K-wires with a Copolymer A coating containing vancomycin showed antimicrobial activity. Control samples comprising a K-wires with a Copolymer A coating but no vancomycin where not efficient confirming that Copolymer A does not provide antimicrobial activity.
  • CFU colony forming units
  • the wires were removed from the wells and osteoblasts were exposed to 5 mg/ml MTT reagent (3- [4,5-dimethylthiazol-2yl]-2,5-diphenyl-tetrazolium bromide) for 4 hours followed by dissolution in dimethyl sulfoxide and measurement of optical density at 570 nm. Six replicates were performed for each of the time periods. Neither the inventive sample nor the PGMA coated wires had an effect on cell proliferation rate. The OD570, which corresponds to the number of living cells, was not significantly different for coated and uncoated wires at different time points.
  • MTT reagent 3- [4,5-dimethylthiazol-2yl]-2,5-diphenyl-tetrazolium bromide

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Abstract

L'invention concerne un implant orthopédique comprenant une surface sur laquelle un revêtement est formé, le revêtement comprenant un copolymère défini par la formule I : Αw-Βx-Cy-Dz dans laquelle : A comprend un groupe époxy ; B comprend un groupe hydrophobe ; C est un agent de réticulation facultatif ; D de formule I comprend un groupe hydrophile ; w représente au moins 0,1 à pas plus de 0,9 à la condition qu'au moins l'un de x ou z ne soit pas égal à zéro ; x vaut jusqu'à 0,9 ; y vaut jusqu'à 0,3 ; et z vaut jusqu'à 0,9.
PCT/US2019/012346 2018-01-05 2019-01-04 Polymères hautement adhérents pour revêtements de dispositif orthopédique Ceased WO2019136247A1 (fr)

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US16/959,562 US20210077668A1 (en) 2018-01-05 2019-01-04 Highly Adherent Polymers for Orthopedic Device Coatings

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US201862613830P 2018-01-05 2018-01-05
US62/613,830 2018-01-05

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US7270678B2 (en) * 2002-06-28 2007-09-18 Bausch & Lomb Incorporated Surface modification of functional group-containing medical devices with catalyst-containing reactive polymer system
US20070166344A1 (en) * 2006-01-18 2007-07-19 Xin Qu Non-leaching surface-active film compositions for microbial adhesion prevention
US8308699B2 (en) * 2008-12-05 2012-11-13 Semprus Biosciences Corp. Layered non-fouling, antimicrobial antithrombogenic coatings

Non-Patent Citations (1)

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